1. Field of the invention
The present invention relates to the preparation of enantiomerically and chemically pure L-pipecolic acid by using optically active resolving agents. The present invention also relates to preparing enantiomerically pure L-N-(2,6-dimethylphenyl)-1-propyl-2-piperidinocarboxamide, its hydrochloride salt, and the hydrochloride monohydrate from L-pipecolic acid.
2. The State of the Art
L-pipecolic acid, also known as piperidino-2-carboxylic acid, is an amino acid, more specifically a cyclic imino acid, that can be isolated from a variety of natural sources. Optically active L-pipecolic acid is used as an intermediate in the synthesis of the local anesthetics, such as levo-bupivacaine and ropivacaine. Ropivacaine is the generic name of the n-propyl homolog of the recently introduced long active local anesthetics having the general formula N-(n-alkyl)-2,6-dimethylpheny-piperidine-2-carboxamide. Optically pure ropivacaine is the levo form of N-(n-propyl)-2,6-dimethylphenyl-piperidine-2-carboxamide. Another chemical name for ropivacaine is (L) N-n-propylpipecolic acid-2,6-xylidide. The optically pure form of ropivacaine is reported to have reduced cardio-toxic potential compared to the racemic mixture of bupivacaine (racemic N-n-butylpipecolic acid-2,6-xylidide, having better analgesic effects than either D or L isomer alone, as described in U.S. Pat. No. 4,695,576)
Based on the biological results of testing (L)-enantiomer of ropivacaine as described in U.S. Pat. No. 4,695,576, it has been reported that L-enantiomers display lower cardiotoxicity than the corresponding racemates whilst maintaining the same anesthetic potency, and are therefore potentially more beneficial for clinical use. Thus it is advantageous to have an efficient and safe process for producing L-ropivacaine and its salts in the form of single enantiomer.
Preparation of optically pure L-pipecolic acid by different methods has been described in the art. Most typically, the art uses an optically pure resolving agent, most commonly optically pure tartaric acid, although enzymatic methods have also been disclosed.
WO 85/00599 and U.S. Pat. No. 4,695,576 each describes a method of preparing L-N-n-propylpipecolic acid-2,6-xylidide by condensing L-pipecolic acid chloride hydrochloride with 2,6-xylidine using L-pipecolic acid having a purity of about 90% (that is, about 90% in the levo form, 90% optical purity). It is disclosed in these patents that the 90% pure L-pipecolic acid was obtained by resolving DL-pipecolic acid with L-tartaric acid alone.
Eur. J. Med. Chem. 33 (1998) 23-31 has described the preparation of L-pipecolic acid by resolving DL-pipecolic acid with only D-(−)-tartaric acid and Amberlite resin. The conditions described for the resolution are seen to be inefficient, presenting low yields. Further, the use of D-tartaric acid alone would be expensive and thus such a process is economically unfeasible.
WO 961185 describes a process for the preparation of optically enriched pipecolic acid as a salt with an optically active acid. Exemplified in this publication is the use of DL-pipecolic acid, D-tartaric acid and butyric acid heated to 110° C. for four hours to form (L)-pipecolic acid-D-tartrate salt which is then converted to (L)-pipecolic acid.
Acta. Chem. Scand. B41: 757-761, 1987 describes use of iso-propanol in combination with various water contents for the resolution step. These combinations gave varying yields and quality. It has been suggested that optical resolution of pipecolic acid xylidines with iso-propanol or ethanol has an increasing yield but a decreasing optical purity as the temperature of the resolution is decreased. “Optical resolutions, theory and practice,” Kozma and Marthi, Scientific Update Training Course (Mayfield, UK), November 2003.
JP 2000178253 describes a method for preparation of optically active pipecolic acid by resolving with optically active 2-phenoxy propionic acid.
Resolution has also been accomplished enzymatically. J. Microb. Biotech. 11 (2) (2001) 217-221 describes a method for optical resolution of DL-pipecolic acid by fermentation using pseudomonas sp. PA09. J. Org. Chem. 59 (8) (1994) 2075-2081 describes a process for the resolution of pipecolic acid using partially purified lipase from Aspergillus niger, yielding 93% enantiomeric excess of (S)-pipecolic acid and this compound needs further purification. J. Biosci. Biotech. Biochem 66 (2002) 622 describes a process for enzymatic conversion of L-lysine to L-pipecolic acid with an enantiomeric purity of 100%. JP 06030789 describes a process for preparing L-pipecolic acid by treating DL-pipecolic acid with D-amino acid oxidase and sodium borohydride.
Unfortunately, none of the foregoing resolution procedures establishes a practical and economic method for obtaining pure L-pipecolic acid having an enantiomeric purity greater than 99%. The conventional resolution processes described in prior art afford up to 90% of the L-isomer of pipecolic acid. Thus a process for preparing pure L-pipecolic acid is very much in need for the economic and safe production of pure pharmacologically active L-Ropivacaine, and its salts (and hydrates thereof).
Some of the disadvantages of these resolution processes described in the prior art are:
(1) Optical resolution of DL-pipecolic acid by the use of either L or D optically active resolving agents results in enantiomeric purity of only about 90% and the product contains D-pipecolic acid as an impurity (U.S. Pat. No. 4,870,086). L-Ropivacaine prepared from 90% optically pure L-pipecolic acid thus requires additional purification at some intermediate stage or at the final stage, thereby leading to lot of yield loss and manufacturing difficulties. The procedure for preparing L-pipecolic acid chloride hydrochloride using phosphorous pentachloride at a temperature of about 35° C. and then further conversion to xylidide at temperature of about 70° C. gives an even lower yield.
(2) L-pipecolic acid prepared by enzymatic conversion of L-Lysine or enzymatic resolution of DL-pipecolic acid method results in 100% enantiomeric purity. However, such methods are expensive and require more controls (and capital investment) for monitoring the reaction.
(3) It has been reported that the L-N-n-propylpipecolicacid-2,6-xylidide hydrochloride described in WO 85/00599 and U.S. Pat. No. 4,695,576 contains 10% of the D-(+) enantiomer of N-n-propylpipecolic acid-2,6-xylidide hydrochloride as an impurity. In addition, the product is hygroscopic, contains 2% water, and is physically unstable.
Most of the synthetic processes reported in the art for preparing Ropivacaine involve the use of a chlorinating agent to condense the L-pipecolic acid with xylidine.
U.S. Pat. No. 4,695,576 describes the use of phosphorus pentachloride in acetyl chloride at a temperature of 35° C. to convert L-pipecolic acid hydrochloride to L-pipecolic acid chloride hydrochloride. The L-pipecolic acid chloride hydrochloride is further condensed with 2,6-xylidine in a mixture of acetone and N-methylpyrrolidone to give L-N-pipecolyxylidide.
U.S. Pat. No. 5,777,124 describes a process for preparing levo-bupivacaine and its analogues by the one pot conversion of L-pipecolic acid to L-N-pipecolyxylidide using hydrochloric acid and thionyl chloride at a temperature of 55° C.
EP 1433782 describes a process for producing pipecolamide derivatives by reacting pipecolic acid and xylidine in presence of a condensation agent such as dicyclohexycarbodiimide, methane sulfonyl chloride, phosphoryl chloride. The reactions were performed at a temperature of 50° C. to room temperature.
The major disadvantages with these synthetic processes are:    (1) The handling of phosphorous pentachloride is problematic on a manufacturing scale at temperatures around 35° C., as in the '576 patent, because of the liberation of acid fumes.    (2) The reaction of L-pipecolic acid chloride hydrochloride with 2,6-xylidine at 70° C. poses problems with the instability of L-pipecolic acid chloride hydrochloride, the yield of L-N-pipecolyxylidide is low, and it is difficult to isolate the product from the reaction medium.    (3) The reaction of L-pipecolic acid chloride hydrochloride with 2,6-xylidine in a mixture of acetone and N-methylpyrrolidone, as advocated in the art, again yields a product that is difficult to isolate from the reaction medium.    (4) The handling of thionyl chloride at a higher temperature suitable for its use at an industrial scale is difficult, requiring special personnel, and the reaction generates harmful gases (posing environmental and safety problems).